Comparative Brain Microanatomical and Neurochemical Alterations Following the Administration of Seven Oral Artemisinin-Based Combination Therapies in Swiss Mice

Abstract

Over a decade after artemisinin-based combination therapy (ACT) approval as the most preferred anti-malarial drug. Seven ACTs can be sourced as over-the-counter medications in most African pharmacies without prescription. A comparative neurotoxicity of these ACTs was investigated in an in vivo experimental model. Swiss mice numbering 40, weighing 18 - 26 g were allotted to eight groups (n = 5). Group 1 (normal control [NC]), received distilled water 10 mL, while groups 2 to 8 were administered (5.71 mg artesunate+amodiaquine [AA]); (19.29 mg artesunate+mefloquine [AM]); (10.36 mg artesunate+sulfadoxine+pyrimethamine [ASP]); (19.29 mg artesunate+pyronaridine [APy]); (12.5 mg artemisinin+piperaquine [AP]); (15.42 mg dihydroartemisinin+piperaquine [DP]); and (8 mg artemether+lumefantrine [AL]) per kg body weights, respectively orally for 3 days, but for 2 days in group 6. Animals were sacrificed 24 hrs after last administration under ketamine anaesthesia (100 mg/kg, i.p), and excised brains were evaluated for neurochemical and neurohistological alterations. Oxidative stress markers: malondialdehyde and reduced glutathione significantly (p < 0.05) increased as well as antioxidant enzymes glutathione peroxidase, catalase, superoxide dismutase in ACT-administered groups compared to NC. Neurohistology of hippocampal cornu ammonis 1 (CA1) and cerebellum demonstrated vacuolations, neuronal hypertrophy and atrophy pyramidal, and Purkinje neurons. Immunohistochemistry with glial fibrillary acidic protein antibody demonstrated mild to mostly severe astrogliosis in the ACT-administered groups. In conclusion, oxidative stress markers and antioxidants were elevated in the order DP>APy>AP>ASP>AA>AL>AM. Together with the neurohistology, neurotoxicity were in the order DP>ASP>APy>AP>AL>AA>AM particularly in the hippocampus compared to the cerebellum. KEYWORDS: Artemisinin-based combination therapies, Cerebellum, CA1 region of the hippocampus, Neurodegeneration, Oxidative stress.